ABSTRACT: Cerebral malaria (CM) is a grave public health problem, often leading to death and permanent neurological damage. Erythropoietin (EPO) has been recently found to have powerful neuroprotective activities. Two labs have shown that recombinant human EPO (rhEPO) increases survival of mice with CM. Elevated EPO has been associated epidemiologically with a reduced incidence of CM in P. falciparum&#8208;infected children. Based on these observations, rhEPO is currently being evaluated as a treatment for CM in a clinical trial. We will investigate the hypothesis that EPO and EPO&#8208;mimetic peptides decrease both the mortality rate and neurological sequelae of CM by down regulating the host innate immune response. The long term goal of this project is to develop an inexpensive synthetic erythropoietin&#8208;mimetic peptide, as an adjunctive treatment for CM in combination with the anti&#8208;malarial drug artesunate. rhEPO may be a useful therapeutic agent for the treatment of CM, however, it is expensive and must be stored at 4C. In contrast, EPO&#8208;mimetic peptides (Epoptides), can be synthesized inexpensively and stored at room temperature. In animal models, Epoptides are neuroprotective, but not hematopoietic and have fewer adverse effects than rhEPO. One Epoptide is currently in clinical development for the treatment of CNS injuries. We have preliminary evidence that another Epoptide prolongs survival in mice with CM. Thus, Epoptides could be an ideal adjunct treatment for CM. Specifically, we will: (1) Investigate effects of rhEPO and on important neurocognitive and neuropathological features of CM using in vitro and in vitro models (2) Identify the most effective EPO&#8208;mimetic peptides against CM using in vitro models. (3) Characterize the most effective EPOmimetic peptides against CM using a murine model. The results of this study, if successful, could serve as the foundation for a future clinical trial. Overall, this study could lead to an important new treatment for CM.